liu.seSearch for publications in DiVA
Change search
Link to record
Permanent link

Direct link
BETA
Alternative names
Publications (10 of 48) Show all publications
Das, J., Verma, D., Gustafsson, M. & Lerm, M. (2019). Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects. Epigenetics, 14(6), 589-601
Open this publication in new window or tab >>Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects
2019 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 6, p. 589-601Article in journal (Refereed) Published
Abstract [en]

The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
DNA methylation; BCG-vaccination; phagocytosis; actin regulation; Mycobacterium tuberculosis; Tuberculosis
National Category
Medical Genetics
Identifiers
urn:nbn:se:liu:diva-158857 (URN)10.1080/15592294.2019.1603963 (DOI)000471388000001 ()31010371 (PubMedID)
Note

Funding Agencies|Hjart-Lungfonden [20150709]; Vetenskapsradet [2012-3349]

Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2019-07-25
Lerm, M. & Dockrell, H. M. (2018). Addressing diversity in tuberculosis using multidimensional approaches. Journal of Internal Medicine, 284(2), 116-124
Open this publication in new window or tab >>Addressing diversity in tuberculosis using multidimensional approaches
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 2, p. 116-124Article, review/survey (Refereed) Published
Abstract [en]

Tuberculosis is a complex disease, which can affect many organs other than the lungs. Initial infection may be cleared without inducing immunological memory, or progress directly to primary disease. Alternatively, the infection may be controlled as latent TB infection, that may progress to active tuberculosis at a later stage. There is now a greater understanding that these infection states are part of a continuum, and studies using PET/CT imaging have shown that individual lung granulomas may respond to infection independently, in an un-synchronized manner. In addition, the Mycobacterium tuberculosis organisms themselves can exist in different states: as nonculturable forms, as persisters, as rapidly growing bacteria and a biofilm-forming cording phenotype. The omics approaches of transcriptomics, metabolomics and proteomics can help reveal the mechanisms underlying these different infection states in the host, and identify biosignatures with diagnostic potential, that can predict the development of disease, in progressors as early as 12-18 months before it can be detected clinically, or that can monitor the success of anti-TB therapy. Further insights can be obtained from studies of BCG vaccination and new TB vaccines. For example, epigenetic changes associated with trained immunity and a stronger immune responses following BCG vaccination can be identified. These omics approaches may be particularly valuable when linked to studies of mycobacterial growth inhibition, as a direct read-out of the ability to control mycobacterial growth. The second generation of omics studies is identifying much smaller signatures based on as few as 3 or 4 genes. Thus, narrowing down omics-derived biosignatures to a manageable set of markers now opens the way to field-friendly point of care assays.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
biomarker; immunity; tuberculosis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-150236 (URN)10.1111/joim.12776 (DOI)000439800900002 ()29804295 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Heart and Lung Foundation (Oscar II Jubilee Foundation); European Commission Horizon2020 program [643381]; Bill and Melinda Gates Foundation (GC6-74) [37772]; Bill and Melinda Gates Foundation (GC6-2013) [OPP1055806]

Available from: 2018-08-22 Created: 2018-08-22 Last updated: 2018-08-30
Brighenti, S. & Lerm, M. (2018). Toward the understanding of human tuberculosis. Journal of Internal Medicine, 284(2), 113-115
Open this publication in new window or tab >>Toward the understanding of human tuberculosis
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 2, p. 113-115Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
Diversity; Host-directed therapy; Multi-drug resistance; Personalized medicine; Protective immunity; Tuberculosis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-150235 (URN)10.1111/joim.12781 (DOI)000439800900001 ()29971845 (PubMedID)
Available from: 2018-08-22 Created: 2018-08-22 Last updated: 2018-08-30
Lerm, M. & Netea, M. G. (2016). Trained immunity: a new avenue for tuberculosis vaccine development. Journal of Internal Medicine, 279(4), 337-346
Open this publication in new window or tab >>Trained immunity: a new avenue for tuberculosis vaccine development
2016 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 4, p. 337-346Article, review/survey (Refereed) Published
Abstract [en]

Adaptive immunity towards tuberculosis (TB) has been extensively studied for many years. In addition, in recent years the profound contribution of innate immunity to host defence against this disease has become evident. The discovery of pattern recognition receptors, which allow innate immunity to tailor its response to different infectious agents, has challenged the view that this arm of immunity is nonspecific. Evidence is now accumulating that innate immunity can remember a previous exposure to a microorganism and respond differently during a second exposure. Although the specificity and memory of innate immunity cannot compete with the highly sophisticated adaptive immune response, its contribution to host defence against infection and to vaccine-induced immunity should not be underestimated and needs to be explored. Here, we present the concept of trained immunity and discuss how this may contribute to new avenues for control of TB.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2016
Keywords
BCG; epigenetics; innate immunity; trained immunity; tuberculosis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-127425 (URN)10.1111/joim.12449 (DOI)000372978800002 ()26602369 (PubMedID)
Available from: 2016-05-01 Created: 2016-04-26 Last updated: 2017-11-30
Braian, C., Svensson, M., Brighenti, S., Lerm, M. & Parasa, V. R. (2015). A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection. Journal of Visualized Experiments (104), 1-9, Article ID e53084.
Open this publication in new window or tab >>A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection
Show others...
2015 (English)In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 104, p. 1-9, article id e53084Article in journal (Refereed) Published
Abstract [en]

Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

Place, publisher, year, edition, pages
JOURNAL OF VISUALIZED EXPERIMENTS, 2015
Keywords
Infection; Issue 104; In vitro model; 3D model; 3D analysis; lung tissue; tuberculosis; M. tuberculosis; granuloma
National Category
Cell and Molecular Biology Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:liu:diva-125330 (URN)10.3791/53084 (DOI)000368572800031 ()26485646 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-1951, 2012-3349]; Swedish Foundation for Strategic Research; Karolinska Institutet; Swedish International Development Cooperation Agency (Sida); Swedish Civil Contingencies Agency (MSB); Swedish Heart and Lung Foundation (HLF); Stockholm County Council

Available from: 2016-02-23 Created: 2016-02-19 Last updated: 2018-01-10
Kumar, M., Sahu, S. K., Kumar, R., Subuddhi, A., Maji, R. K., Jana, K., . . . Basu, J. (2015). MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway.. Cell host & microbe, 17(3), 345-56
Open this publication in new window or tab >>MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway.
Show others...
2015 (English)In: Cell host & microbe, ISSN 1934-6069, Vol. 17, no 3, p. 345-56Article in journal (Refereed) Published
Abstract [en]

The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-κB pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1β, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1β. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.

Place, publisher, year, edition, pages
elsevier, 2015
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-116362 (URN)10.1016/j.chom.2015.01.007 (DOI)000350979800013 ()25683052 (PubMedID)
Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-01-11Bibliographically approved
Larsson, M. C., Lerm, M., Ängeby, K., Nordvall, M., Jureen, P. & Schön, T. (2014). A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability. Journal of Microbiological Methods, 106, 146-150
Open this publication in new window or tab >>A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability
Show others...
2014 (English)In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 106, p. 146-150Article in journal (Refereed) Published
Abstract [en]

The intracellular (IC) effect of drugs against Mycobacterium tuberculosis (Mtb) is not well established but increasingly important to consider when combining current and future multidrug regimens into the best possible treatment strategies. For this purpose, we developed an IC model based on a genetically modified Mtb H37Rv strain, expressing the Vibrio harvei luciferase (H37Rv-lux) infecting the human macrophage like cell line THP-1. Cells were infected at a low multiplicity of infection (1:1) and subsequently exposed to isoniazid (INH), ethambutol (EMB), amikacin (AMI) or levofloxacin (LEV) for 5 days in a 96-well format. Cell viability was evaluated by Calcein AM and was maintained throughout the experiment. The number of viable H37Rv-lux was determined by luminescence and verified by a colony forming unit analysis. The results were compared to the effects of the same drugs in broth cultures. AMI, EMB and LEV were significantly less effective intracellularly (MIC90: greater than4 mg/L, 8 mg/L and 2 mg/L, respectively) compared to extracellularly (MIC90: 0.5 mg/L for AMI and EMB; 0.25 mg/L for LEV). The reverse was the case for INH (IC: 0.064 mg/L vs EC: 0.25 mg/L). In conclusion, this luciferase based method, in which monitoring of cell viability is included, has the potential to become a useful tool while evaluating the intracellular effects of anti-mycobacterial drugs.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Tuberculosis; Levofloxacin; Drug susceptibility testing; Intracellular; Luminescence; Minimal inhibitory concentration
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-112299 (URN)10.1016/j.mimet.2014.08.015 (DOI)000343358200024 ()25194234 (PubMedID)
Note

Funding Agencies|Swedish Heart and Lung Foundation (Oscar II Jubilee Foundation); Marianne and Marcus Wallenberg Foundation; Research Council of Southeast Sweden (FORSS)

Available from: 2014-11-24 Created: 2014-11-24 Last updated: 2018-01-11Bibliographically approved
Pienaar, E. & Lerm, M. (2014). A mathematical model of the initial interaction between Mycobacterium tuberculosis and macrophages. Journal of Theoretical Biology, 342, 23-32
Open this publication in new window or tab >>A mathematical model of the initial interaction between Mycobacterium tuberculosis and macrophages
2014 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 342, p. 23-32Article in journal (Refereed) Published
Abstract [en]

There is a large body of literature describing molecular level interactions between Mycobacterium tuberculosis (Mtb) and macrophages. Macrophages initiate a range of anti-bacterial mechanisms in response to infection, and Mtb is capable of surviving and circumventing many of these responses. We apply a computational approach to ask: what are the effects on the cellular level of these opposing interactions? The model considers the interplay between bacterial killing and the pathogen's interference with macrophage function. The results reveal an oscillating balance between host and pathogen, but the balance is transient and varies in length, indicating that stochasticity in the bacterial population or host response could contribute to the diverse incubation periods observed in exposed individuals. The model captures host and strain variation and gives new insight into host-pathogen compatibility and co-evolution.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Variable diseaseoutcomes, Macrophage function, Individual-based model
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99946 (URN)10.1016/j.jtbi.2013.09.029 (DOI)000330257900003 ()24112967 (PubMedID)
Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2017-12-06
Abuzeid, N., Kalsum, S., Koshy, R. J., Larsson, M. C., Glader, M., Andersson, H., . . . Lerm, M. (2014). Antimycobacterial activity of selected medicinal plants traditionally used in Sudan to treat infectious diseases. Journal of Ethnopharmacology, 157, 134-139
Open this publication in new window or tab >>Antimycobacterial activity of selected medicinal plants traditionally used in Sudan to treat infectious diseases
Show others...
2014 (English)In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 157, p. 134-139Article in journal (Refereed) Published
Abstract [en]

Ethnopharmacological relevance: The emergence of multidrug-resistant strains of Mycobacterium tuberculosis underscores the need for continuous development of new and efficient methods to determine the susceptibility of isolates of Mycobacterium tuberculosis in the search for novel antimycobacterial agents. Natural products constitute an important source of new drugs, and design and implementation of antimycobacterial susceptibility testing methods are necessary to evaluate the different extracts and compounds. In this study we have explored the antimycobacterial properties of 50 ethanolic extracts from different parts of 46 selected medicinal plants traditionally used in Sudan to treat infectious diseases. Materials and methods: Plants were harvested and ethanolic extracts were prepared. For selected extracts, fractionation with hydrophilic and hydrophobic solvents was undertaken. A luminometry-based assay was used for determination of mycobacterial growth in broth cultures and inside primary human macrophages in the presence or absence of plant extracts and fractions of extracts. Cytotoxicity was also assessed for active fractions of plant extracts. Results: Of the tested extracts, three exhibited a significant inhibitory effect on an avirulent strain of Mycobacterium tubercluosis (H37Ra) at the initial screening doses (125 and 6.25 mu g/ml). These were bark and leaf extracts of Khaya senegalensis and the leaf extract of Rosmarinus officinalis L. Further fractions of these plant extracts were prepared with n-hexane, chloroform, ethyl acetate, n-butanol, ethanol and water, and the activity of these extracts was retained in hydrophobic fractions. Cytotoxicity assays revealed that the chloroform fraction of Khaya senegalensis bark was non-toxic to human monocyte-derived macrophages and other cell types at the concentrations used and hence, further analysis, including assessment of IC50 and intracellular activity was done with this fraction. Conclusion: These results encourage further investigations to identify the active compound(s) within the chloroform fraction of Khaya senegalensis bark. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Mycobacterium tuberculosis; Sudanese medicinal plants; Primary human macrophages; Luminescence reporter assay; Cytotoxicity assay
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113785 (URN)10.1016/j.jep.2014.09.020 (DOI)000347022700016 ()25261689 (PubMedID)
Note

Funding Agencies|Ekhaga Foundation [2011-33]; Swedish Insitute

Available from: 2015-02-02 Created: 2015-01-30 Last updated: 2019-01-07
Andersson, H., Eklund, D., Ngoh, E., Persson, A., Andersson, B., Svensson, K., . . . Stendahl, O. (2014). Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages. PLoS ONE, 9(7), e101514
Open this publication in new window or tab >>Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages
Show others...
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e101514-Article in journal (Refereed) Published
Abstract [en]

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during tuberculosis. Innate immune cells such as macrophages and neutrophils are first recruited to the site of infection, and mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Such anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens. We therefore investigated how uptake of apoptotic neutrophils by Mtb-activated human monocyte-derived macrophages modulates their function. We show that Mtb infection exerts a potent pro-inflammatory activation of human macrophages with enhanced gene activation and release of several cytokines (TNF, IL-1ß, IL-6, IL-18 and IL-10). This response was augmented by apoptotic neutrophils. Macrophages containing both Mtb and apoptotic cells showed a stronger cytokine expression than non-infected cells. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response, which can contribute to the early control of Mtb infection.

Place, publisher, year, edition, pages
PLoS, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100888 (URN)10.1371/journal.pone.0101514 (DOI)000338637300054 ()
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2017-12-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5092-9892

Search in DiVA

Show all publications